3.2. Chemistry
3.2.1. General Procedure for the Synthesis of Compounds (3–7)
To a mixture of pyridazin-3(2H)-one (1) (1 mmol) and sodium methanoate (0.065 g, 1.2 mmol) in 30 mL of dry ethanol, aromatic aldehyde (2) (1 mmol) was added drop-wise. The mixture was refluxed for 6 h, then left under stirring overnight at room temperature. After cooling, the mixture was acidified with concentrated HCl. The precipitate formed was filtered, washed with water, and recrystallized from ethanol to afford the pure products (3–7).
4-(4-methylbenzyl)-6-phenylpyridazin-3(2H)-one (3): White solid, Yield = 78%, m.p = 276 °C, FT-IR (ATR, cm−1): 3304 (NH), 3130–2846 (CH), 1647 (C=O), 1600 (N=C); 1H NMR (500 MHz, DMSO-d6) δ: 2.40 (s, 3H, CH3), 2.96 (s, 2H, CH2-Ar), 7.32–7.50 (m, 7H, H-Ar), 7.70 (d, 2H, J = 8.4 Hz, 2H, H-Ar), 7.88 (s, 1H, CH-pyr), 10.82 (s, 1H, CONH); ESI-MS: calculated for C18H16N2O [M + H]+: 275.1300, found: 275.0509.
4-(4-chlorobenzyl)-6-phenylpyridazin-3(2H)-one (4): White solid, Yield = 72%; m.p = 296 °C; FT-IR (ATR, cm−1): 3304 (NH), 3124–2893 (CH), 1647 (C=O), 1600 (N=C); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 2.96 (s, 2H, CH2-Ar), 7.38–7.45 (m, 3H, H-Ar), 7.61 (d, 2H, J = 8.4 Hz, H-Ar), 7.70 (d, 2H, J = 8.4 Hz, H-Ar), 7.80 (d, 2H, J = 8.4 Hz, H-Ar), 7.90 (s, 1H, CH-pyri), 10.84 (s, 1H, CONH); ESI-HRMS: calculated for C17H13ClN2O [M + H]+: 297.0715, found: 297.1030.
4-(2,6-dichlorobenzyl)-6-phenylpyridazin-3(2H)-one (5): Brown solid, Yield = 94%, mp = 165 °C, FT-IR (ATR, cm−1): 3206 (NH), 3061–2875 (CH), 1646 (C=O), 1605 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.55–7.53 (m, 2H, H-Ar), 7.53 (d, J = 2.1 Hz, 2H, H-Ar), 7.41–7.35 (m, 4H, H-Ar), 6.89 (s, 1H, H-Pyz),4.10 (s, 2H, NCH2CO); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 160.77, 144.32, 140.31, 135.15, 133.23, 130.63, 129.77, 129.56, 129.44, 129.32, 126.06, 125.95, 31.44. ESI-HRMS: calculated for C17H12Cl2N2O [M + H]+: 331.0350, found: 331.0020.
4-(2-nitrobenzyl)-6-phenylpyridazin-3(2H)-one (6): Brown solid, Yield = 96%; mp = 170 °C, FT-IR (ATR, cm−1): 3200 (NH), 3043–2865 (CH), 1646 (C=O), 1595 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 8.21 (d, J = 2.0 Hz, 1H, H-Ar), 8.05 (ddd, J = 8.3, 2.4, 1.0 Hz, 1H, H-Ar), 8.03 (s,1H, H-pyr), 7.81–7.78 (m, 3H, H-Ar), 7.56 (t, J = 7.9 Hz, 1H, H-Ar), 7.46–7.42 (m, 2H, H-Ar), 7.41–7.37 (m, 1H, H-Ar), 3.97 (s, 2H, CH2-Ar); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 161.09, 148.32, 144.64, 141.94, 141.01, 136.41, 135.28, 130.36, 129.72, 129.42, 129.36, 126.21, 124.17, 122.10, 35.40. HRMS: calculated for C17H13FN2O [M − H]−: 306.0315, found: 306.0475.
4-(4-fluorobenzyl)-6-phenylpyridazin-3(2H)-one (7): White solid, Yield = 58%, m.p = 280 °C, FT-IR (ATR, cm−1): 3296 (NH), 1740 (C=O), 1652 (N=C); 1H NMR (500 MHz, DMSO-d6) δ: 2.94 (s, 2H, CH2-Ar), 7.17–7.20 (m, 2H, H-Ar), 7.38–7.44 (m, 3H, H-Ar), 7.70 (d, 2H, J = 8.4 Hz, H-Ar), 7.78 (m, 2H, H-Ar), 7.88 (s, 1H, H-pyri), 10.82 (s, 1H, CONH); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 161.84, 158.31, 144.20, 142.41, 135.90, 135.68, 132.94, 129.66, 129.85, 129.51, 129.54, 129.51, 127.57, 35.31. ESI-HRMS: calculated for C17H13N3O3 [M + H]+: 281.1018, found: 281.3045.
3.2.2. General Procedure for the Synthesis of Compounds (8–12)
Ethyl bromoacetate (0.53, 3.2 mmol) was added drop-wise to a solution of compounds (3–7) (3 mmol), K2CO3 (1.24 g, 9 mmol), and tetra n-butylammonium bromide (TBAB) as a catalyst in dry THF (20 mL), and the mixture was refluxed for 6 h. After the end of the reaction, the formed salts were removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethylacetate:hexane (1:1)) to give pure esters (8–12).
Ethyl 2-(5-(4-methylbenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetate (8): White crystals, Yield = 71%, m.p = 120 °C, FT-IR (ATR, cm−1): 3489 (OH), 3078–2852 (CH), 1751, 1652 (C=O), 1607 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.91 (s, 1H,CH-pyri), 7.82 (d, J = 7.8 Hz, 2H, H-Ar), 7.51–7.43 (m, 3H, H-Ar) 7.24 (d, J = 7.9 Hz, 2H, H-Ar), 7.11 (d, J = 7.8 Hz, 2H, 2H, H-Ar), 4.94 (s, 2H, NCH2CO), 4.16 (q, J = 7.1 Hz, 2H,CH2CH3), 3.87 (s, 2H,CH2-Ar), 1.19 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 167.86, 159.48, 143.74, 142.56, 135.50, 134.69, 134.24, 129.40, 128.97, 128.85, 128.03, 125.79, 61.10, 53.99, 35.03, 20.57, 13.91. HRMS: calculated for C22H22N2O3 [M + H]+: 363.1794, found: 363.1689.
Ethyl 2-(5-(4-chlorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetate (9): White solid, Yield = 92%; m.p = 142 °C, FT-IR (ATR, cm−1): 3466 (OH), 3067–2864 (CH), 1745, 1647 (C=O), 1607 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 8.02 (s, 1H,CH-pyri), 7.85 (d, J = 7.8 Hz, 2H, H-Ar), 7.54–7.44 (m, 3H, H-Ar), 7.40 (d, J = 8.7 Hz, 2H, H-Ar), 7.35 (d, J = 8.6 Hz, 2H, H-Ar),7.43–7.31 (m, 4H, H-Ar), 4.96 (s, 2H, NCH2CO), 4.16 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.92 (s, 2H, CH2-Ar), 1.19 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 167.48, 159.29, 143.74, 141.76, 136.85, 134.21, 131.21, 130.83, 129.41, 128.84, 128.44, 128.29, 125.82, 61.08, 53.82, 34.86, 13.91. HRMS: calculated for C21H19ClN2O3 [M + 3H]+: 385.1166, found: 385.1512.
Ethyl 2-(5-(2,6-dichlorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetate (10): White solid, Yield = 78%; m.p = 80 °C, FT-IR (ATR, cm−1): 3304 (OH), 3067–2870 (CH), 1757, 1659 (C=O), 1612 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.58–7.55 (m, 2H, H-Ar), 7.49 (d, J = 8.1 Hz, 2H, H-Ar), 7.38–7.32 (m, 4H, H-Ar), 6.97 (s, 1H, CH-pyri), 5.02 (s, 1H, NCH2CO), 4.28 (s, 1H, CH2-Ar), 4.24 (q, J = 7.0 Hz), 1.27 (t, J = 7.1 Hz); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 167.84, 160.38, 145.27, 140.10, 136.03, 134.57, 133.05, 129.60, 129.39, 128.66, 128.55, 126.31, 125.71, 61.58, 54.03, 31.00, 13.10. HRMS: calculated for C21H18Cl2N2O3 [M + H]+: 417.0796, found: 417.0757.
Ethyl 2-(5-(2-nitrobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetate (11): Brown solid, Yield = 85%; m.p = 175 °C, FT-IR (ATR, cm−1): 3211–2887 (CH), 1647 (C=O), 1607 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 8.22 (t, J = 1.9 Hz, 1H, H-Ar), 8.14 (s, CH-pyri), 8.06 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H, H-Ar), 7.84–7.81 (m, 2H, H-Ar), 7.80 (dt, J = 7.7, 1.2 Hz, 1H, H-Ar), 7.56 (t, J = 8.0 Hz, 1H, H-Ar), 7.49–7.41 (m, 3H, H-Ar), 4.90 (s, 2H, NCH2CO), 4.09 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.02 (s, 2H, CH2-Ar), 1.12 (t, J = 7.1 Hz, 3H, CH2CH3). 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 168.06, 159.82, 148.33, 144.37, 141.58, 140.73, 136.46, 134.71, 130.37, 130.10, 129.61, 129.48, 126.46, 124.28, 122.18, 61.65, 54.44, 35.72, 14.47. HRMS: calculated for C21H18N3O4 [M + 2H]+: 395.1307, found: 395.1144.
Ethyl 2-(5-(4-fluorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetate (12): White solid, Yield = 88%, m.p = 73 °C, FT-IR (ATR, cm−1): 3484 (OH), 3067–2835 (CH), 1757, 1652 (C=O), 1600 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.58–7.54 (m, 4H, H-Ar), 7.45–7.35 (m, 5H, H-Ar), 6.93 (s, 1H, CH-pyri), 4.90 (s, 2H, NCH2CO), 4.10 (q, J = 7.1 Hz, 2H, CH2CH3), 3.87 (s, 2H, CH2-Ar), 1.14 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 166.46, 159.57, 143.65, 139.80, 135.91, 134.84, 130.68, 129.94, 129.55, 129.36, 126.26, 125.76, 61.64, 54.40, 35.99, 14.50. HRMS: calculated for C21H18FN2O· [M + H]+: 367.1435, found: 367.1427.
3.2.3. General Procedure for the Synthesis of Compounds (13–17)
To a solution of esters (8–12) (3.6 mmol) in ethanol (50 mL), was added 6 N NaOH (14.4 mmol) and the mixture was stirred at room temperature for 4 h. The solvent was then evaporated and the residue was diluted with cold water, and acidified with 6 N HCl. The final product was filtered off by suction filtration and recrystallized from dry ethanol. The precipitate formed was filtered off and recrystallized from dry ethanol to give the corresponding acids (13–17).
2-(5-(4-methylbenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetic acid (13): White solid, Yield = 90%, m.p = 170 °C, FT-IR (ATR, cm−1): 3461 (OH), 3072–2843 (CH), 1757, 1734 (C=O), 1654 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.91 (s, 1H, CH-pyri), 7.82 (d, J = 7.1 Hz, 2H, H-Ar), 7.54–7.43 (m, 3H, H-Ar), 7.25 (d, J = 7.7 Hz, 2H, H-Ar), 7.12 (d, J = 7.7 Hz, 2H, H-Ar), 4.87 (s, 2H, NCH2CO), 3.87 (s, 2H, CH2-Ar), 2.27 (s, 3H,CH3). 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 168.95, 159.37, 143.47, 142.53, 135.47, 134.76, 134.37, 129.34, 128.99, 128.90, 128.86, 127.87, 125.78, 53.73, 35.07, 20.62; HRMS: calculated for C19H18N2O3 [M + H]+: 335.1160, found: 335.1378.
2-(5-(4-chlorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetic acid (14): White solid, Yield = 84%, m.p = 174 °C (EtOH), FT-IR (ATR, cm−1): 3461 (OH), 3055–2852 (CH), 1751, 1647 (C=O), 1600 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.99 (s, 1H, CH-pyri), 7.84 (dd, J = 7.8, 1.6 Hz, 2H, H-Ar), 7.54–7.44 (m, 3H, H-Ar), 7.41 (d, J = 8.7 Hz, 2H, H-Ar), 7.36 (d, J = 8.7 Hz, 2H, H-Ar), 4.81 (s, 2H, NCH2CO), 3.71 (s, 2H, CH2-Ar); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 169.23, 159.29, 143.28, 141.66, 137.02, 134.41, 131.13, 130.87, 129.31, 128.86, 128.31, 128.14, 125.79, 54.15, 34.88. HRMS: calculated for C19H15ClN2O3 [M + H]+: 354.9932, found: 354.9837.
2-(5-(2,6-dichlorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetic acid (15): White solid, Yield = 89%; m.p = 140 °C, FT-IR (ATR, cm−1): 3461 (OH), 3055–2852 (CH), 1751, 1647 (C=O), 1600 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.65–7.60 (m, 2H, H-Ar), 7.57 (d, J = 7.8 Hz, 2H, H-Ar), 7.48–7.40 (m, 4H, H-Ar), 7.03 (s, 1H, CH-pyri), 4.95 (s, 1H, NCH2CO), 4.19 (s, 1H, CH2-Ar); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 168.89, 158.91, 143.24, 139.37, 135.34, 134.10, 132.49, 130.06, 129.43, 128.95, 128.75, 125.70, 125.51, 53.76, 31.40. HRMS: calculated for C19H14Cl2N2O3 [M − H]−: 387.0468, found: 386.9793.
2-(5-(2-nitrobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetic acid (16): Yellow solid, Yield = 80%; m.p = 102 °C (EtOH), FT-IR (ATR, cm−1): 3465 (OH), 3050–2865 (CH), 1756, 1650 (C=O), 1610 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 8.21 (t, J = 1.9 Hz, 1H, H-Ar), 8.13 (s, CH-pyri), 8.07–8.04 (m, 1H, H-Ar), 7.84–7.78 (m, 3H, H-Ar), 7.56 (t, J = 7.9 Hz, 1H, H-Ar), 7.49–7.41 (m, 3H, H-Ar), 4.87 (s, 2H, NCH2CO), 3.98 (s, 2H, CH2-Ar); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 168.10, 159.75, 148.83, 144.30, 141.27, 140.85, 136.82, 134.86, 130.31, 130.17, 129.77, 129.13, 126.46, 124.44, 121.23, 54.65, 35.48. HRMS: calculated for C19H15N3O5 [M + 2H]+: 367.1073, found: 367.1427.
2-(5-(4-fluorobenzyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)acetic acid (17): Brown solid, Yield = 86%, m.p = 187 °C, FT-IR (ATR, cm−1): 3460 (OH), 3085–2842 (CH), 1750, 1649 (C=O), 1598 (C=N); 1H NMR (500 MHz, DMSO-d6, δ (ppm)) δ: 7.68–7.55 (m, 5H, H-Ar), 7.48–7.40 (m, 4H, H-Ar), 7.04 (s, 1H, CH-pyr), 4.94 (s, 2H, NCH2CO), 3.20 (s, 2H, CH2-Ar); 13C NMR (101 MHz, DMSO-d6, δ (ppm)) δ: 168.85, 158.91, 143.24, 139.37, 135.35, 134.13, 132.51, 130.07, 129.43, 128.97, 128.76, 125.71, 125.52, 53.75, 31.40. HRMS: calculated for C19H15FN2O3 [M + H]+: 339.1101, found: 339.1997.